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The fatty acid amide hydrolase inhibitor URB597 modulates serotonin-dependent emotional behaviour, and serotonin1A and serotonin2A/C activity in the hippocampus.

The fatty acid amide hydrolase (FAAH) inhibitor URB597 increases anandamide, resulting in antidepressant/anxiolytic-like activity, likely via CB1 receptor-mediated modulation of serotonin (5-HT) and norepinephrine (NE) neurotransmission. However, the relative importance of the 5-HT and NE systems in these effects and on effects of URB597 on postsynaptic 5-HT receptors remain to be determined. Using behavioural and electrophysiological approaches, we assessed the effects of acute-single and repeated URB597 treatment on responses predicting antidepressant/anxiolytic activity, and on hippocampal

Beneficial effects of natural phenolics on levodopa methylation and oxidative neurodegeneration.

Levodopa (L-DOPA) is widely used for symptomatic management in Parkinson's disease. We recently showed that (-)-epigallocatechin-3-gallate, a tea polyphenol, not only inhibits L-DOPA methylation, but also protects against oxidative hippocampal neurodegeneration. In the present study, we sought to determine several other common dietary phenolics, namely, tea catechins [(+)-catechin and (-)-epicatechin] and a representative flavonoid (quercetin), for their ability to modulate L-DOPA methylation and to protect against oxidative hippocampal injury. A combination of in vitro biochemical assays, cel

Desensitization of somatostatin-induced inhibition of low extracellular magnesium concentration-induced calcium spikes in cultured rat hippocampal neurons.

Neuronal excitability is inhibited by somatostatin, which might play important roles in seizure and neuroprotection. The possibility of whether the effect of somatostatin on neurotransmission is susceptible to desensitization was investigated. We tested the effects of prolonged exposure to somatostatin on 0.1 mM extracellular Mg(2+) concentration ([Mg(2+)](o))-induced intracellular free Ca(2+) concentration ([Ca(2+)](i)) spikes in cultured rat hippocampal neurons using fura-2-based microfluorimetry. Reducing [Mg(2+)](o) to 0.1 mM elicited repetitive [Ca(2+)](i) spikes. These [Ca(2+)](i) spikes

Chronic treatment with supraphysiological levels of corticosterone enhances D-MDMA-induced dopaminergic neurotoxicity in the C57BL/6J female mouse.

Chronic stress and extended periods of elevated circulating glucocorticoids have been reported to exacerbate excitotoxicity-induced hippocampal neuronal injury in rat. Despite continued interest in the effects of protracted exposure to stress or glucocorticoids, there has been little examination of how other types of neurotoxicity may be exacerbated or blocked, by stress. Here we examined the effects of chronic supraphysiologic levels of corticosterone on D-3,4-methylenedioxymethamphetamine (D-MDMA)-induced striatal dopaminergic neurotoxicity in the female C57BL/6J mouse. Corticosterone (5 mg,

Chronic L-DOPA administration is not toxic to the remaining dopaminergic nigrostriatal neurons, but instead may promote their functional recovery, in rats with partial 6-OHDA or FeCl(3) nigrostriatal lesions.

In this study, we have examined the effects of chronic L-3,4-dihydroxyphenylalanine (L-DOPA) administration on the remaining dopaminergic neurons in rats with 6-hydroxydopamine (6-OHDA) or buffered FeCl(3) partial lesions to the nigrostriatal tract. L-DOPA administration increased the turnover of dopamine in the striatum. L-DOPA administration for 1 week produced an increase in the level of striatal RTI-121 binding, a specific marker for dopamine uptake sites on the dopaminergic nerve terminals in the striatum. However, longer periods of L-DOPA treatment decreased the level of RTI-121 binding

Nerve injury increases an excitatory action of neuropeptide Y and Y2-agonists on dorsal root ganglion neurons.

Damage to sensory nerves invokes the expression of neuropeptide Y in the cell bodies of sensory neurons in dorsal root ganglia. We therefore compared the action of this peptide on control dorsal root ganglia neurons with its action on neurons from animals in which the sciatic nerve had been cut. Neuropeptide Y (0.1-1.0 microM) increased the excitability of 24% of control neurons and its effect was stronger and more cells (56%) were affected after axotomy. Increased excitability was mediated via a Y2-receptor and resulted from attenuation of Ca2+-sensitive K+-conductance(s) secondary to suppres

In a model of Batten disease, palmitoyl protein thioesterase-1 deficiency is associated with brown adipose tissue and thermoregulation abnormalities.

Infantile neuronal ceroid lipofuscinosis (INCL) is a fatal neurodegenerative disorder caused by a deficiency of palmitoyl-protein thioesterase-1 (PPT1). We have previously shown that children with INCL have increased risk of hypothermia during anesthesia and that PPT1-deficiency in mice is associated with disruption of adaptive energy metabolism, downregulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), and mitochondrial dysfunction. Here we hypothesized that Ppt1-knockout mice, a well-studied model of INCL that shows many of the neurologic manifestations of the d

Social defeat stress induces hyperthermia through activation of thermoregulatory sympathetic premotor neurons in the medullary raphe region.

Psychological stress-induced hyperthermia is a fundamental autonomic response in mammals. However, the central circuitry underlying this stress response is poorly understood. Here, we sought to identify sympathetic premotor neurons that mediate a hyperthermic response to social defeat stress, a psychological stress model. Intruder rats that were defeated by a dominant resident conspecific exhibited a rapid increase in abdominal temperature by up to 2.0  °C. In these defeated rats, we found that expression of Fos, a marker of neuronal activation, was increased in the rostral medullary raphe reg

Intrinsic membrane properties of locus coeruleus neurons in Mecp2-null mice.

Rett syndrome caused by mutations in methyl-CpG-binding protein 2 (Mecp2) gene shows abnormalities in autonomic functions in which brain stem norepinephrinergic systems play an important role. Here we present systematic comparisons of intrinsic membrane properties of locus coeruleus (LC) neurons between Mecp2(-/Y) and wild-type (WT) mice. Whole cell current clamp was performed in brain slices of 3- to 4-wk-old mice. Mecp2(-/Y) neurons showed stronger inward rectification and had shorter time constant than WT cells. The former was likely due to overexpression of inward rectifier K(+) (K(ir))4.1

Astroglial and microglial activation in the wistar rat ventral tegmental area after a single striatal injection of 6-hydroxydopamine.

Astroglial and microglial activation were analyzed in the ventral tegmental area (VTA) in adult male Wistar rats, after an unilateral striatal 6-hydroxydopamine (6-OHDA) injection. Different doses (8, 4, and 1 microg) of 6-OHDA were injected in the left side of the neostriatum; animals were sacrificed 22 days later. Control animals received an injection of the same volume of the solvent. The tyrosine hydroxylase (TH) positive dopamine cells, the glial fibrillary acidic protein (GFAP) immuno -labeled astrocytes, and the OX42 immunoreactive microglia were visualized by means of immunohistochemis

Characterization of opioid receptors modulating the function of capsaicin-sensitive neurons in guinea-pig atria.

Transmural nerve stimulation of isolated atria, obtained from reserpine-pretreated guinea-pigs, in the presence of atropine and the beta 1-adrenoceptor-blocking drug CGP 20712A, induced a positive inotropic effect. [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin (DAGO), [D-Ala2,D-Leu5]enkephalin (DADLE), morphine and dynorphin dose dependently reduced the cardiac response to transmural nerve stimulation. The delta receptor selective agonist [D-Pen2,D-Pen5]enkephalin (DPDPE), and the kappa receptor agonist, U50488, were unable modify the response. The inhibitory effect of all the active opioid agonists wa

Identification of G-protein coupled receptor kinase 2 in paired helical filaments and neurofibrillary tangles.

G-protein coupled receptor kinases (GRKs) constitute a serine/threonine kinase family playing a major role in agonist-induced phosphorylation and desensitization of G-protein coupled receptors. Recently, GRK2 and GRK5 have been demonstrated to phosphorylate alpha-synuclein (Ser129) and other synuclein isoforms. We studied colocalization of GRK2, GRK5, alpha-synuclein, and tau in neurodegenerative disorders characterized by fibrillary tau inclusions and/or alpha-synuclein-enriched Lewy bodies. We found that Lewy bodies were negative for both GRK2 and GRK5 in Lewy body disease (LBD) and LBD mixe

Pharmacological and genetic analysis of mechanisms underlying detrusor overactivity in rats.

AIMS: Suprapontine lesions, such as those resulting from cerebrovascular disease, cause bladder storage dysfunction. Detrusor overactivity (DO) following cerebral infarction may be explained by impairment of the suprapontine regulatory system. However, precise mechanisms underlying DO is not clear. The following studies were undertaken to examine pharmacological and genetic mechanisms of DO in rats. RESULTS AND CONCLUSIONS: Mechanisms of long-lasting DO in rats with cerebral infarction require signal transfer, which begins with the opening of glutamate receptors at the dorsal pontine tegmentu

Physiological properties of hypothalamic MCH neurons identified with selective expression of reporter gene after recombinant virus infection.

Neurons that synthesize melanin-concentrating hormone (MCH) may modulate arousal and energy homeostasis. The scattered MCH neurons have been difficult to study, as they have no defining morphological characteristics. We have developed a viral approach with AAV for selective long-term reporter gene (GFP) expression in MCH neurons, allowing the study of their cellular physiology in hypothalamic slices. MCH neurons showed distinct membrane properties compared to other neurons infected with the same virus with a cytomegalovirus promoter. Transmitters of extrahypothalamic arousal systems, including

Local opioid withdrawal in rat single periaqueductal gray neurons in vitro.

Opioid dependence in ventrolateral periaqueductal gray (PAG) neurons was studied by using intracellular recordings from brain slices. In slices from morphine-dependent rats maintained in morphine (5 microM) in vitro, action potential frequencies of opioid-sensitive neurons did not differ from untreated control neurons but were greater than in control neurons maintained in morphine in vitro, indicating development of tolerance. Naloxone (100 nM or 1 microM) depolarized 25 of 51 neurons from morphine-dependent rats maintained in morphine in vitro, 19 of which previously had been classified as op

Peripheral Nerves in Cancer: Regulatory Roles and Therapeutic Strategies.

Cancer neuroscience has emerged as a transformative frontier in oncology research, focusing on the interplay between cancer cells and the nervous system. Cancer cells establish tumorspecific neural networks within tumor tissues via neurotrophic hijacking. The nervous system regulates tumor initiation, progression, and metastasis either directly by regulating signal transduction in tumor cells or indirectly by modulating the tumor microenvironment (TME). The positive feedback loop between cancer cells and nerves promotes tumor progression. Deciphering the regulatory role of nerves in tumor prog

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… In 2019, Mauffrey et al. reported that DCX‐positive neural progenitor cells from the central nervous system (CNS) can traverse the blood–brain barrier and migrate to prostate cancer tissues through the bloodstream and reside in the tumor tissues, where they generate new adrenergic neurons that may contribute …

Dopaminergic modulation of GABAergic transmission in the entorhinal cortex: concerted roles of α1 adrenoreceptors, inward rectifier K⁺, and T-type Ca²⁺ channels.

Whereas the entorhinal cortex (EC) receives profuse dopaminergic innervations from the midbrain, the effects of dopamine (DA) on γ-Aminobutyric acid (GABA)ergic interneurons in this brain region have not been determined. We probed the actions of DA on GABAA receptor-mediated synaptic transmission in the EC. Application of DA increased the frequency, not the amplitude, of spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSCs) recorded from entorhinal principal neurons, but slightly reduced the amplitude of the evoked IPSCs. The effects of DA were unexpectedly found to be mediated by α1 adrenor

Echinacoside's nigrostriatal dopaminergic protection against 6-OHDA-Induced endoplasmic reticulum stress through reducing the accumulation of Seipin.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Recent epidemiological studies suggest that echinacoside (ECH), a phenylethanoid glycoside found in Cistanche deserticola, has a protective effect against the development of PD. However, the detailed mechanisms of how ECH suppresses neuronal death have not been fully elucidated. In this study, we confirmed that ECH protects nigrostriatal neurons against 6-hydroxydopamine (6-OHDA)-induced endoplasmic reticulum stress (ERS) in vivo and in vitro. ECH rescued cell viability in damaged cells and decreased 6-OHDA-induced

A Gαs DREADD mouse for selective modulation of cAMP production in striatopallidal neurons.

Here, we describe a newly generated transgenic mouse in which the Gs DREADD (rM3Ds), an engineered G protein-coupled receptor, is selectively expressed in striatopallidal medium spiny neurons (MSNs). We first show that in vitro, rM3Ds can couple to Gαolf and induce cAMP accumulation in cultured neurons and HEK-T cells. The rM3Ds was then selectively and stably expressed in striatopallidal neurons by creating a transgenic mouse in which an adenosine2A (adora2a) receptor-containing bacterial artificial chromosome was employed to drive rM3Ds expression. In the adora2A-rM3Ds mouse, activation of r

Exogenous and endogenous ghrelin in gastroprotection against stress-induced gastric damage.

Ghrelin, identified in the gastric mucosa has been involved in control of food intake and growth hormone (GH) release but little is known about its influence on gastric secretion and mucosal integrity. The effects of ghrelin on gastric secretion, plasma gastrin and gastric lesions induced in rats by 75% ethanol or 3.5 h of water immersion and restraint stress (WRS) were determined. Exogenous ghrelin (5, 10, 20, 40 and 80 microg/kg i.p.) increased gastric acid secretion and attenuated gastric lesions induced by ethanol and WRS and this was accompanied by the significant rise in plasma ghrelin l